One very common form of drug-drug interactions occurs when one drug enhances the metabolism of a second unrelated drug. Recent in vitro and in vivo data have demonstrated that many of these interactions are mediated via the orphan nuclear receptor SXR (Steroid and Xenobiotic Receptor). SXR binds to and is activated by a wide array of drugs leading to enhanced transcription of CYP3A4. Since CYP3A4 metabolizes approximately 50 percent of pharmaceutical agents, SXR ligands can have widespread effects on drug metabolism. Moreover, recent results have shown that hyperforin, the active ingredient in the commonly used herbal St. John's Wort, is an extremely potent SXR ligand, indicating that common herbal remedies can have direct effects on this drug metabolizing pathway. We present preliminary data indicating that SXR can have even wider effects on drug clearance. For example, we show that SXR activates expression of CYP2C8 and P-glycoprotein, the product of the MDR1 gene. These findings extend the role of SXR to include additional drug metabolism pathways as well as drug efflux. Since SXR is a highly promiscuous xenobiotic receptor, it is likely to be activated by many yet-to-be examined herbal agents. Thus, we propose to test the ability of other herbal remedies to activate SXR. In addition, we propose to identify other SXR- regulated genes, particularly those involved in drug clearance. Finally, while SXR can be activated by a variety of foreign compounds, its endogenous ligand remains to be determined. This implies that certain herbals could promote drug interactions by stimulating or inhibiting the production of this endogenous ligand. We have identified an endogenous fraction that can activate SXR and we propose to purify and characterize this compound. These studies will provide a molecular basis for understanding and predicting botanical-drug interactions.